Study suggests association

Action Points

Note that this large, Danish, observational study found that hormonal contraceptive use was associated with depression.

Although causality can not be inferred, the authors note some dose-response effects in certain classes of contraceptives which might argue for a more direct link with depression.

Women who used hormonal contraception were associated with an increased risk of depression compared to non-hormonal contraception users, a large prospective Danish cohort study found.

Rates of women filling their first prescription for an antidepressant were highest among women using medroxyprogesterone acetate depot (Depo Provera), contraceptive implants and the norgestrolmin transdermal patch, reported Charlotte Wessel Skovlund, MSc, of University of Copenhagen, and colleagues.

Depression rates also varied by age, with adolescents using hormonal contraception also associated with higher rates of depression than adult women, the authors wrote in JAMA Psychiatry.

Skovlund and colleagues explained recent research that has suggested the link between hormonal contraception and depression may center around the role of estrogen and progesterone and their influence on the cortical and subcortical regions of the brain, which are responsible for emotional processing.

"Because mood symptoms are a known reason for cessation of hormonal contraceptive use [and] hormonal contraception introduces synthetic hormones and modulates the internal hormone production, an examination of the influence of hormonal contraceptives on women's mood is warranted," they wrote.

The Danish Sex Hormone Register Study is an ongoing study, with this examined cohort comprised of girls age 15 through women age 34. The authors examined data from 1,061,997 women, with a mean age of 24 years. They were followed up for a mean duration of 6 years, and 55.5% were users of hormonal contraception.

Overall, women who took any combined oral contraception or a progestin-only pill were associated with a significantly higher rate of a first use antidepressant versus non-hormonal contraceptive users (adjusted RR 1.2, 95% CI 1.22-1.25 and adjusted RR 1.3, 95% CI 1.27-1.40, respectively).

But contraceptive injections, implants, patches, or rings contraceptives were associated with the highest rates of antidepressant use, including:

However, the authors noted that the increased risks associated with the transdermal patch and vaginal ring may have been a question of dose rather than the route of administration.

These findings were particularly significant among adolescent women. Use of non-oral contraceptive products, such as the etonogestrel vaginal ring and the levonorgestrel intrauterine system were associated with a more than threefold increase of first use antidepressants, with progestin-only pills linked to a more than twofold increase (adjusted RR 2.2, 95% CI 1.99-2.52) compared to non-hormonal contraceptive users.

Risks of first antidepressant use increased from the time of first hormonal contraceptive use, peaking at 6 months of use (adjusted RR 1.4, 95% CI 1.34-1.46), but declined up through the end of patient follow-up (7 to less than 10 years).

The authors used two measures to identify incident depression: first redeemed prescription for antidepressants and "first discharge diagnosis of depression from the Psychiatric Central Register,"which includes both outpatients and inpatients. Overall, study participants filled 133,178 first prescriptions of antidepressants and had 23,077 diagnoses of depression.

Limitations to the study include that because hormonal contraception is not prescribed to women with existing depression, there may be a potential underestimation of the relative risks, as well as potential detection bias because prescribers are more likely to be aware that patients are at risk for depressive symptoms.

The authors recommended further study on depression as an adverse effect of hormonal contraceptive use, but hypothesized their results were not surprising based on the role of different hormones in the cause of depression.

"[Our] finding complies with the theory of progesterone involvement in the etiology of depression, because progestin dominates combined and progestin-only contraceptives," they concluded.

This study was supported in part by the Danish government.

Ms. Wessel Skovlund reported no relevant financial relationships.

Other co-authors reported receiving support from Lundbeck, AstraZeneca, and Exeltis.

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